Colorectal cancer, or cancer of the colon and rectum, is the second leading cause of cancer-related deaths in the United States, and the third most common cancer overall. The American Cancer Society estimates that each year more than 50,000 Americans die from colorectal cancer and approximately 155,000 new cases are diagnosed, accounting for 15% of all types of tumor. Eighty to 90 million Americans (approximately 25% of the U.S. population) are considered at risk because of age or other factors. More women over the age of 75 die from colorectal cancer than from breast cancer. The 5-year survival rate remains at approximately 45%.
The exact causes of colorectal cancer are unknown, but the disease appears to be caused by both inherited and lifestyle factors. Known predisposing conditions for colorectal cancer include familial adenomatous polyposis (FAP), hereditary nonpolyposis colon cancer (HNPCC), Lynch I Syndrome, Lynch II Syndrome, family cancer syndromes, adenomatous polyps (sessile or tubular), and inflammatory bowel disease, including both chronic ulcerative colitis (UC) and Crohn's disease.
Autoimmunity has been emphasized in the pathogenesis of UC. Autoimmune responses (both humoral and cellular) against human tropomyosin (TM) isoform 5 (hTM5) in UC have been reported (Gastroenterology 114:912, 1998, Clinical Immunology 101:289, 2001). hTM 5 is the predominant TM in colon epithelial cells and is expressed on the colon epithelial cell surface which may be critical for autoimmune effector response.
WO 03/007890, the contents of which are incorporated herein by reference in their entirety, discloses a novel hTM isoform, TC22. TC22 is strongly associated with colonic neoplasia and carcinoma (with almost 100% sensitivity) but is not detected in normal colon epithelium (Gastroenterology 123:152, 2002). TC22 is identical to hTM5 apart from the C-terminal domain. Recently, a pilot study of non-dysplastic, colonic tissues from UC and normal subjects showed that TC22 expression was associated with UC complicated with primary sclerosing cholangitis and long standing pancolitis—the two conditions known to be strongly associated with colon cancer in UC (Xin, Jeng et al., “Expression of a Novel Biomarker in Colonic Mucosa of Patients with Ulcerative Colitis At High Risk For Colon Cancer,” Gastroenterology vol. 126, T1229 (2004)).
U.S. Pat. Nos. 5,498,608 and 5,905,073 disclose the use of 2-hydroxy-5-phenylazobenzoic acid derivatives as colon cancer chemopreventive and chemotherapeutic agents. However, the mechanism by which these chemotherapeutic agents operate is not entirely understood.